Complement deficiency promotes cutaneous wound healing in mice

TY - JOUR

T1 - Complement deficiency promotes cutaneous wound healing in mice

AU - Rafail, Stavros

AU - Kourtzelis, Ioannis

AU - Foukas, Periklis G

AU - Markiewski, Maciej M

AU - DeAngelis, Robert A

AU - Guariento, Mara

AU - Ricklin, Daniel

AU - Grice, Elizabeth A

AU - Lambris, John D

N1 - Copyright © 2015 by The American Association of Immunologists, Inc.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - Wound healing is a complex homeostatic response to injury that engages numerous cellular activities, processes, and cell-to-cell interactions. The complement system, an intricate network of proteins with important roles in immune surveillance and homeostasis, has been implicated in many physiological processes; however, its role in wound healing remains largely unexplored. In this study, we employ a murine model of excisional cutaneous wound healing and show that C3(-/-) mice exhibit accelerated early stages of wound healing. Reconstitution of C3(-/-) mice with serum from C3(+/+) mice or purified human C3 abrogated the accelerated wound-healing phenotype. Wound histology of C3(-/-) mice revealed a reduction in inflammatory infiltrate compared with C3(+/+) mice. C3 deficiency also resulted in increased accumulation of mast cells and advanced angiogenesis. We further show that mice deficient in the downstream complement effector C5 exhibit a similar wound-healing phenotype, which is recapitulated in C5aR1(-/-) mice, but not C3aR(-/-) or C5aR2(-/-) mice. Taken together, these data suggest that C5a signaling through C5aR may in part play a pivotal role in recruitment and activation of inflammatory cells to the wound environment, which in turn could delay the early stages of cutaneous wound healing. These findings also suggest a previously underappreciated role for complement in wound healing, and may have therapeutic implications for conditions of delayed wound healing.

AB - Wound healing is a complex homeostatic response to injury that engages numerous cellular activities, processes, and cell-to-cell interactions. The complement system, an intricate network of proteins with important roles in immune surveillance and homeostasis, has been implicated in many physiological processes; however, its role in wound healing remains largely unexplored. In this study, we employ a murine model of excisional cutaneous wound healing and show that C3(-/-) mice exhibit accelerated early stages of wound healing. Reconstitution of C3(-/-) mice with serum from C3(+/+) mice or purified human C3 abrogated the accelerated wound-healing phenotype. Wound histology of C3(-/-) mice revealed a reduction in inflammatory infiltrate compared with C3(+/+) mice. C3 deficiency also resulted in increased accumulation of mast cells and advanced angiogenesis. We further show that mice deficient in the downstream complement effector C5 exhibit a similar wound-healing phenotype, which is recapitulated in C5aR1(-/-) mice, but not C3aR(-/-) or C5aR2(-/-) mice. Taken together, these data suggest that C5a signaling through C5aR may in part play a pivotal role in recruitment and activation of inflammatory cells to the wound environment, which in turn could delay the early stages of cutaneous wound healing. These findings also suggest a previously underappreciated role for complement in wound healing, and may have therapeutic implications for conditions of delayed wound healing.

KW - Animals

KW - Complement C3/deficiency

KW - Complement C5a/genetics

KW - Complement System Proteins/deficiency

KW - Disease Models, Animal

KW - Humans

KW - Inflammation/genetics

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Models, Immunological

KW - Neovascularization, Physiologic/genetics

KW - Receptors, Complement/genetics

KW - Skin/immunology

KW - Wound Healing/genetics

U2 - 10.4049/jimmunol.1402354

DO - 10.4049/jimmunol.1402354

M3 - Article

C2 - 25548229

SN - 0022-1767

VL - 194

SP - 1285

EP - 1291

JO - Journal of Immunology

JF - Journal of Immunology

IS - 3

ER -